Cyclooxygenase-2 (COX-2) is overexpressed in many human and animal cancers. Selective COX-2 inhibitors have shown antitumoral effects in tumors with a high expression of COX-2. This study evaluates (1) the expression of COX-2 in rabbit uterine adenocarcinomas, (2) the correlation between immunophenotypic expression and histopathological changes, and (3) the post-surgery response to therapy with COX-2 inhibitors. Forty rabbit uteri were divided into three groups: neoplastic, hyperplastic, and normal endometrium. A histological and immunohistochemical score was applied to investigate the tumor's grade and the COX-2 expression. By histological evaluation, 30 cases of endometrial adenocarcinoma, 5 cases of endometrial hyperplasia and 5 normal endometria were found. Of the six cases of endometrial adenocarcinoma with follow-up available, four received a post-surgical treatment with meloxicam and two were treated by surgery alone. The survival time of the animals treated with meloxicam was longer than that observed in the untreated animals. A statistically significant difference in COX-2 IHS was observed between non-neoplastic endometrium and adenocarcinoma. The progressive increase in COX-2 expression from normal epithelium to carcinoma suggests that upregulation of COX-2 expression may play a role in tumor initiation and progression. Our findings suggest the possible use of COX-2 inhibitors in treating uterine adenocarcinoma in rabbits. Further study will be needed to confirm this hypothesis.